A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer

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• dc.contributor.author Srinivasan, Srilakshmi
• dc.contributor.author Kogevinas, Manolis
• dc.contributor.author Batra, Jyotsna
• dc.date.accessioned 2025-01-20T06:50:10Z
• dc.date.available 2025-01-20T06:50:10Z
• dc.date.issued 2024
• dc.description.abstract Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The 'Thr' PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.
• dc.format.mimetype application/pdf
• dc.identifier.citation Srinivasan S, Kryza T, Bock N, Tse BWC, Sokolowski KA, Janaththani P, et al. A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer. Nat Commun. 2024 Nov 6;15(1):9587. DOI: 10.1038/s41467-024-52472-6
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-024-52472-6
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/69169
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2024 Nov 6;15(1):9587
• dc.rights © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Cancer genetics
• dc.subject.keyword Genetic association study
• dc.subject.keyword Prostate cancer
• dc.subject.keyword Proteases
• dc.subject.keyword Tumour biomarkers
• dc.title A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion